Alzheimer's disease is the most common neurodegenerative disease. Pathologically, Alzheimer's disease is characterized by neuronal loss in the context of amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed of a small peptide, Abeta, which is formed from a larger precursor protein (APP). Neurofibrillary tangles are formed from abnormally phosphorylated and aggregated tau protein. Genetic evidence implicates abnormalities in APP processing in familial Alzheimer's disease. Mutations in the tau gene cause frontotemporal dementia. Despite identification of these critical genetic linkages, we still know very little about the molecular and biochemical events mediating neuronal dysfunction and death in Alzheimer's disease and frontotemporal dementia. To enable a comprehensive genetic analysis of these disorders, we have developed genetic models in Drosophila melanogaster. Expression of wild type and mutant human tau in transgenic flies truncates life span, and produces adult onset neurodegeneration associated with abnormally phosphorylated tau. These features replicate key manifestations of human neurodegenerative diseases associated with abnormal tau deposition. We now propose to exploit the genetic potential of the system by generating second site suppressors and enhancers of tau-induced neurodegeneration. Existing collections of well-defined mutant chromosomes will be assayed for their ability to alter the neurodegeneration. De novo mutations will also be generated and tested. Modifiers of neurodegeneration will be characterized molecularly. Mammalian homologues of these Drosophila modifiers will be human disease gene candidates and likely components of mammalian neurodegenerative pathways. We will also test the role of candidate modifiers, including chaperones and the ubiquitination/proteosome pathway in tau-induced neurodegeneration. In addition, we have created a genetic system for studying APP processing. The extracellular and transmembrane regions of APP were fused to green fluorescent protein (GFP) and a nuclear localization signal. Transgenic flies were created that show presenilin dependent nuclear localization of GFP. We will use our easily monitored, presenilin dependent cleavage assay to identify new proteins required for APP processing. These novel modifiers will represent candidate members of the presenilin complex, as well as upstream regulatory factors.